Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The effects of nitric oxide (NO) on vascular reactivity and platelet function in the obese (cp/cp) and lean (+/?) JCR:LA-cp rats were investigated. 2. Phenylephrine (PE; 0.1 nM-10 microM) induced contraction of isolated aortic rings in both genotypes (cp/cp and +/?) of JCR:LA-cp rats. The sensitivity to contraction with PE was enhanced in cp/cp compared with +/? rings. Rings from both genotypes showed an increased contraction upon removal of the endothelium. 3. Acetylcholine (ACh; 0.1 nM-10 microM)-induced endothelium-dependent relaxation of rings was not significantly different in the two genotypes. Both were inhibited to a similar extent by NG-nitro-L-arginine methyl ester (L-NAME; 0.01-1 mM) when administered in vitro. 4. The nitric oxide synthase (NOS) inhibitor (L-NAME; 0.3, 1 or 3 mg ml(-1), p.o.) when administered in vivo increased blood pressure in cp/cp rats but not in +/? rats. 5. L-NAME resulted in greater inhibition of ACh-induced relaxation in cp/cp rings compared with +/? rings. 6. L-NAME treatment in vivo caused a decrease in cyclic GMP and NOS activity in rings from cp/cp but not +/? rats. 7. The NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 0.1 nM-10 microM)-induced relaxation of rings from +/? rats, an effect enhanced by the treatment with L-NAME in vivo. 8. Oral administration of L-NAME did not enhance the vasorelaxant effect of SNAP on rings of aorta from cp/cp animals. 9. Platelet aggregation and NOS activity were similar in both genotypes and were not modified by oral administration of L-NAME. 10. These results show that unimpaired generation of NO is crucial for maintenance of vascular tone particularly under conditions of vascular insult exemplified by insulin resistance, obesity and dyslipidemia detected in cp/cp rats.
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PMID:Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin-resistant, obese JCR:LA-cp rats. 964 54

Insulin resistance and hypertension, as well as dyslipidemia, frequently cooccur. Evidence that nitric oxide (NO) plays a crucial role in the long-term regulation of systolic blood pressure led us to examine whether enhanced vasoconstriction and hypertension induced by NO synthase inhibitor could lead to insulin and lipid disorders. NG-Nitro-L-arginine methyl-ester (L-NAME), an inhibitor of NO synthase, was given for 4 weeks in drinking water (100 mg/kg/day) to 12 Sprague-Dawley rats. Another nine rats received both L-NAME and verapamil (100 mg/kg/day), whereas 12 animals fed rat chow only served as controls. Systolic blood pressure was measured weekly by the indirect tail cuff method. Blood samples were taken at the beginning of the experiment, and after 2 and 4 weeks from all rats. The samples were assayed for insulin, glucose, and triglyceride concentrations. L-NAME treatment resulted in a marked and sustained increase in systolic blood pressure from 130+/-7 to 171+/-3 mm Hg by the second week, which was succeeded by a significant elevation in insulin level at the end of 4 weeks, from 2.3+/-1.8 to 5.4+/-2.0 ng/mL. Triglycerides and glucose were unaffected throughout the experiment. The combination of L-NAME and the NO-independent vasodilator, verapamil, attenuated the hypertension induced by L-NAME and prevented the following rise in insulin level. Data suggest that chronic elimination of NO after chronic inhibition of NO synthase may lead to a state of hyperinsulinemia, possibly as an outcome of insulin resistance.
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PMID:Chronic hypertension leads to hyperinsulinemia in Sprague-Dawley rats treated with nitric oxide synthase inhibitor. 975

Cerebrovascular risk factors, including hypertension, smoking, diabetes mellitus, aging, dyslipidemia, and hyperhomocyst(e)inemia are linked to endothelial dysfunction. Endothelial-derived nitric oxide (NO) has inhibitory effects on key processes in atherothrombosis. Although asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is associated with atherosclerotic disease, there has been no report on association of ADMA with ischemic stroke. Here we investigated the relation of plasma ADMA, stroke, and homocyst(e)inemia in the elderly. Plasma ADMA and homocyst(e)ine concentration was determined using high-performance liquid chromatography and fluorescence detection. Patients with ischemic stroke had significantly higher concentrations of plasma ADMA than controls (1.85+/-1.32 vs. 0.93+/-0.32 micromol/l, P=0.0001). After adjustment for risk factors, elevated ADMA levels, above 90th percentile of normal controls (> or =1.43 micromol/l) was associated with stroke (OR=6.05, 95% CI; 2.77-13.3, P=0.02). ADMA plasma levels were positively correlated to homocyst(e)ine levels (r=0.43, P=0.01). Multiple logistic regression analysis revealed that hyperhomocyst(e)inemia (plasma homocyst(e)ine concentration > or =15.0 micromol/l) was a significant predictor of elevated ADMA level. Altogether, findings indicate that elevated ADMA concentrations are at increased risk for ischemic stroke in the elderly, and may account for increased risk of stroke in patients with hyperhomocyst(e)inemia.
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PMID:Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke. 1158 22

Studies using both in vitro and in vivo techniques have repeatedly shown that endothelium-dependent vasodilation (EDV) is impaired in different forms of experimental as well as human hypercholesterolemia. Clearly this impaired EDV can be reversed by lowering cholesterol levels by diet or medical therapy. Competitive blocking of L-arginine, changes in nitric oxide synthase activity, increased release of endothelin-1, and inactivation of nitric oxide due to superoxide ions all contribute to the impairment in EDV during dyslipidemia. The oxidation of low density lipoprotein, with its compound lysophosphatidylcholine, plays a critical role in these events. However, data on the role of triglycerides and fat-rich meals regarding EDV are not so consistent as data for cholesterol, although a view that the compositions of individual fatty acids and antioxidants are of major importance is emerging. Thus, this review shows that while impaired EDV is a general feature of hypercholesterolemia, the mechanisms involved and the therapeutic opportunities available still have to be investigated. Furthermore, discrepancies regarding the role of triglycerides and fat content in food may be explained by divergent effects of different fatty acids on the endothelium.
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PMID:Lipids and endothelium-dependent vasodilation--a review. 1187 56

Males are at greater risk for renal injury than females. This may relate to nitric oxide (NO) availability, because female rats have higher renal endothelial NO synthase (NOS) levels. Previously, our laboratory found susceptibility to proteinuria induced by NOS inhibition in male compared with female rats. Dyslipidemia and hypercholesterolemia dose dependently decreased renal NOS activity and caused renal injury in female rats. We hypothesized that exposure of male rats to hypercholesterolemia would lead to more renal injury in male than in female rats due to an a priori lower renal NO system. Female and male rats were fed no, low-dose, or high-dose cholesterol for 24 wk. Cholesterol feeding dose dependently increased proteinuria in both female and male rats, but male rats developed more proteinuria at similar plasma cholesterol (P < 0.001). Control males had lower renal NOS activity than control females (4.44 +/- 0.18 vs. 7.46 +/- 0.37 pmol. min(-1). mg protein(-1); P < 0.05), and cholesterol feeding decreased renal NOS activity in males and in females (P < 0.05). Cholesterol-fed males developed significantly more vascular, glomerular, and tubulointerstitial monocyte/macrophage influx and injury than females. Thus under baseline conditions, male rats have lower renal NOS activity than female rats. This may explain why male rats are more sensitive to renal injury by factors that decrease NO availability, such as hypercholesterolemia.
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PMID:Male gender increases sensitivity to renal injury in response to cholesterol loading. 1248 46

Vascular and neurologic impairment remain an important source of morbidity in patients with chronic renal failure (CRF). A portion of CRF patients still suffers from uremic encephalopathy or other signs of nervous system impairment. Several reports demonstrate increased incidence of cardiac infarction and cerebrovascular accidents in CRF patients, even in those with otherwise adequate dialysis treatment [1]. Premature vascular disease, including myocardial infarction, stroke, and peripheral vascular disorder, are the leading causes of death in this population. Although several traditional risk factors for vascular disease and endothelial dysfunction, including smoking, diabetes, dyslipidemia, and hypertension, are often increased in CRF, these factors can only partly explain the high vasculopathy-related morbidity and mortality. Several authors have postulated that CRF-associated atherosclerosis and endothelial dysfunction result from accumulation of certain 'uremic factors,' the identities of which are still a matter of debate. These factors include a variety of guanidino compounds (GCs), which have been shown to be nitric oxide synthase (NOS) modulators both in vitro and in vivo. However, other effects of accumulated uremic GCs have been identified.
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PMID:Nitric oxide in uremia: effects of several potentially toxic guanidino compounds. 1269 2

Despite significant progress in renal replacement therapy, the mortality from cardiovascular disease (CVD) in patients with chronic renal failure (CRF) is many times higher than in the general population. The traditional risk factors are frequently present in CRF patients. However, based upon conventional risk factor analysis, these factors do not fully explain the extraordinary increase in morbidity and mortality in CVD among patients with CRF. Accumulating evidence suggests that CRF is associated with impaired endothelial cell function. In recent years, the role of endothelial dysfunction (ED) and excessive oxidative stress (OS) in the development of CVD has been highlighted. ED is an early feature of vascular disease in different diseases such diabetes, hypertension, hypercholesterolemia, and coronary heart disease. The precise mechanism which induces ED is not clear. Several factors however, including OS-related accumulation of uremic toxins, hypertension and shear stress, dyslipidemia with cytotoxic lipoprotein species such as small, dense low-density lipoprotein (LDL) particles, competitive inhibition of endothelial nitric oxide (NO) by increased production by asymmetrical dimethylarginine (ADMA) are pathogenic. In addition, it is known that excessive OS causes ED. An overproduction of reactive oxygen species (ROS) may injure the endothelial cell membrane, inactivate NO, and cause oxidation of an essential cofactor of nitric oxide synthase (NOS). Recent studies have demonstrated that an impaired endothelium-dependent vasodilation and OS are closely related to each other in patients with CRF.
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PMID:Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: impact on cardiovascular disease. 1269 8

Asymmetric dimethylarginine (ADMA) is an emerging cardiovascular risk factor. Its increased levels have been hypothesized to be a cause of endothelial dysfunction in pathological conditions such as hypertension, dyslipidemia, renal failure, hyperglycemia, and hyperhomocysteinemia. It acts as a potent competitive inhibitor of nitric oxide synthase. Methods using ortho-phthaldialdehyde (OPA) as derivatization reagent are widely performed in HPLC determination of ADMA, but they produce derivatives whose fluorescence rapidly decreases during time. Moreover, these methods do not allow a clear separation of ADMA from its stereoisomer symmetric dimethylarginine (SDMA). Our work describes a new method to determine ADMA, SDMA, and arginine that uses, as derivatizing reagent, naphthalene-2,3-dicarboxaldehyde (NDA). Chromatograms with low background, showing a complete separation of ADMA and SDMA, are obtained. NDA derivatives are considerably more stable than the OPA derivatives. The calibration curves of ADMA and SDMA are linear within the range of 0.01-16.0 microM. Coefficients of variation are less than 1.7% for within day and less then 2.3% for day to day. Absolute mean recoveries from supplemented samples are between 100 and 104%. These characteristics make this method reliable and easily manageable for large routine analyses.
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PMID:High-performance liquid chromatographic assay of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine in human plasma by derivatization with naphthalene-2,3-dicarboxaldehyde. 1278 25

Subclinical hypothyroidism (sHT) is associated with enhanced cardiovascular risk. To test the hypothesis that patients with sHT are characterized by endothelial dysfunction and impaired nitric oxide (NO) availability, in 14 patients [serum cholesterol, 218 +/- 41 mg/dl (5.6 +/- 0.9 mM)] and 28 euthyroid subjects, subdivided into groups A and B [serum cholesterol, 170 +/- 19 mg/dl (4.4 +/- 0.5 mM) and 217 +/- 21 mg/dl (5.6 +/- 0.5 mM), respectively], we studied the forearm blood flow (strain-gauge plethysmography) response to intrabrachial acetylcholine, an endothelium-dependent vasodilator, at baseline and during infusion of N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor. Response to sodium nitroprusside and minimal forearm vascular resistances were also evaluated. In sHT patients, vasodilation to acetylcholine was reduced, compared with group B (+358 +/- 29% vs. +503 +/- 19%, P = 0.0003) and group A (663 +/- 65%, P = 0.02 vs. group B and P = 0.0002 vs. sHT). L-NMMA blunted the vasodilation to acetylcholine in groups A and B (49.1 +/- 6.3% and 42.7 +/- 5.5% maximal forearm blood flow reduction, respectively, P < 0.0001 vs. acetylcholine), whereas it was ineffective in sHT patients (12.8 +/- 2.5%). Response to sodium nitroprusside and minimal vascular resistances were similar. In sHT (n = 9) patients, 6 months of euthyroidism by levothyroxine replacement increased acetylcholine-vasodilation and restored L-NMMA inhibition. Patients with sHT are characterized by endothelial dysfunction resulting from a reduction in NO availability, an alteration partially independent of dyslipidemia and reversed by levothyroxine supplementation.
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PMID:Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. 1291 62

Insulin-mediated glucose disposal varies widely in apparently healthy human beings, and the more insulin resistant an individual, the more insulin they must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. These changes increase risk of cardiovascular disease (CVD), and in 1988, this cluster of related abnormalities was designated as comprising a syndrome (X). Several other clinical syndromes are now known to be associated with insulin resistance and compensatory hyperinsulinemia. For example, polycystic ovary syndrome appears to be secondary to insulin resistance and compensatory hyperinsulinemia. More recently, studies have shown that the prevalence of insulin resistance/hyperinsulinemia is increased in patients with nonalcoholic fatty liver disease, and there are reports that certain forms of cancer are more likely to occur in insulin resistant/hyperinsulinemic persons. Finally, there is substantial evidence of an association between insulin resistance/hyperinsulinemia, and sleep disordered breathing. Given the rapid increase in the number of clinical syndromes and abnormalities associated with insulin resistance/hyperinsulinemia, it seems reasonable to suggest that the cluster of these changes related to the defect in insulin action be subsumed under the term of the insulin resistance syndrome. In addition to the identification of additional clinical syndromes related to insulin resistance/hyperinsulinemia, a number of new risk factors have been recognized that would increase CVD risk in these individuals. Thus, in addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin resistant/hyperinsulinemic individuals also includes the appearance of smaller and denser low density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. Evidence is also accumulating that sympathetic nervous system (SNS) activity is increased in insulin resistant, hyperinsulinemic individuals, and, along with the salt sensitivity associated with insulin resistance/hyperinsulinemia, increases the likelihood that these individuals will develop essential hypertension. The first step in the process of atherogenesis is the binding of mononuclear cells to the endothelium, and mononuclear cells isolated from insulin resistant/hyperinsulinemic individuals adhere with greater avidity. This process is modulated by adhesion molecules produced by endothelial cells, and there is a significant relationship between degree of insulin resistance and the plasma concentration of the several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine, an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulin resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin resistant subjects. It is obvious that the cluster of abnormalities associated with insulin resistance and compensatory hyperinsulinemia contains many well-recognized CVD risk factors, choosing which one, or ones, that are primarily responsible for the accelerated atherogenesis that characterizes this syndrome is not a simple task. Indeed, efforts to try to do so by the use of multiple regression analysis of epidemiological data may be more misleading than helpful.
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PMID:Insulin resistance, the insulin resistance syndrome, and cardiovascular disease. 1648 19


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